KR101858055B1 - Composition for ameliorating cognitive functions comprising tamsulosin - Google Patents
Composition for ameliorating cognitive functions comprising tamsulosin Download PDFInfo
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- KR101858055B1 KR101858055B1 KR1020150109919A KR20150109919A KR101858055B1 KR 101858055 B1 KR101858055 B1 KR 101858055B1 KR 1020150109919 A KR1020150109919 A KR 1020150109919A KR 20150109919 A KR20150109919 A KR 20150109919A KR 101858055 B1 KR101858055 B1 KR 101858055B1
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- tamsulosin
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
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Abstract
The present invention relates to a composition for improving cognitive function comprising tomrosin as an active ingredient. More specifically, the present invention relates to a method for inducing the generation of neural tissue without changing the cell death level and selectively increasing the current magnitude of the ion channel by the NMDA receptor to improve memory, learning ability, and spatial perception ability The present invention relates to a pharmaceutical composition for improving the cognitive function, which comprises Shin as an active ingredient, a pharmaceutical composition for preventing or treating neurodegenerative diseases, and a health food composition. The present inventive testosterone selectively increases the current magnitude of the ion channel by the NMDA receptor, thereby improving memory, learning ability, and spatial perception ability. Therefore, it is useful for improving cognitive function and further applicable to treatment of neurodegenerative diseases have.
Description
The present invention relates to a composition for improving cognitive function comprising tamsulosin as an active ingredient. More specifically, the present invention relates to a method for inducing the generation of nerve tissue without changing the cell death level and selectively increasing the current magnitude of the ion channel by the NMDA receptor to improve memory, learning ability, and spatial perception ability The present invention relates to a pharmaceutical composition for improving the cognitive function, a composition for preventing or treating neurodegenerative diseases, and a health food composition.
The human brain is an important part of learning, memory, and exercise. Neurons are connected to each other to form a huge neural network, which is a neural basis that includes learning and memory. Brain cells present in the nervous system recurrently undergo differentiation growth and destruction from the time of childhood, and promote cell growth through natural environment, food, exercise and training processes, or cause oxidative damage to cells due to various causes, Necrosis also occurs. In children with vigorous activity of brain cells, not only brain cell differentiation occurs well, but also growth and judgment are enhanced, memory is improved, and learning ability is improved. On the other hand, as age increases, brain function decreases, concentration becomes weaker, and various cognitive functions such as depressed memory or learning ability are reduced by various causes such as external factors such as stress.
In order to solve such a problem, there have been many published patents related to composition that improve cognitive function in Korea. For example, Publication No. 2014-0144785 discloses a composition for improving memory and learning ability comprising an extract of citrus peel as an active ingredient. In Publication No. 2014-0142630, there is disclosed a composition containing a lotus root extract as an active ingredient, A pharmaceutical composition for the treatment of functional food and memory damage is disclosed. In Publication No. 2014-0132469, there is disclosed a memory and concentration-enhancing composition containing a mixed extract consisting of Ganoderma lucidum, Angelicae gigantis, Bacillus subtilis, Seok Changpo and Deer antler. Although chemical agents and natural compositions that improve cognitive function have been shown in the market, there have not been developed excellent agents with high efficacy yet, and it is reported that chemical agents cause many side effects such as hepatotoxicity, insomnia, hypertension and vomiting have. Therefore, it is required to develop a preparation having an excellent effect for improving the cognitive function while having few side effects.
On the other hand, tamsulosin is a drug classified as one of alpha-1-adrenergic antagonists and is currently reported to be used to reduce excretory urinary tract or to stabilize related symptoms in patients with symptoms of hyperplasia of the prostate (Barendrecht et al., 2008 Reference). In particular, studies in humans have reported that weektime frequency, nocturia, and urinary incontinence are significantly reduced by treatment with alpha 1-adrenergic antagonists (see Athanasopoulos et al., 2003) (See Jeong and Lee, 2000). In addition, some studies have reported that the use of antimuscarinic and alpha 1-adrenergic antagonists together in humans improves OAB symptoms (Athanasopoulos and Perimenis, 2005; Kaplan et al., 2008) . As such, it is generally recognized that tamsulosin is still considered to be one of the most commonly used drugs for patients with benign prostatic hyperplasia.
Recently, however, the present inventors have found that tamsulosin, which is widely known as an effective drug for the treatment of benign prostatic hyperplasia (BPH) symptoms, does not change its cell death rate in the hippocampal dentate gyrus, And it has a new use for improving the cognitive function by selectively increasing the current size of the ion channel by the NMDA receptor to improve the memory ability, the learning ability and the spatial perception ability, and to complete the present invention It came. These results suggest that tamsulosin can be used as a composition to improve cognitive function through NMDA receptors.
It is an object of the present invention to provide a pharmaceutical composition for improving cognitive function comprising tamsulosin as an active ingredient.
Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising tamsulosin as an active ingredient.
It is still another object of the present invention to provide a health food composition for improving cognitive function comprising tamsulosin as an active ingredient.
In one aspect of the present invention, the present invention provides a pharmaceutical composition for improving the cognitive function comprising tamsulosin as an active ingredient.
The term "tamsulosin" in the present invention is also referred to as an alpha-adrenergic receptor antagonist or antagonist, alpha blocker, which is used for the treatment of symptoms of benign prostatic hyperplasia (BPH). In the present invention, the term antagonist means a substance that acts antagonist to a receptor of a certain agonist (agonist) but does not exhibit physiological action through each receptor.
In the present invention, the term "cognition" refers to all the processes of thinking, speaking, remembering, judging, and practicing using the brain with the ability to efficiently manipulate knowledge and information. Specifically, the cognitive function may be memory, learning or spatial perception. Specifically, the memory may be a long-term memory or a short-term memory, and more specifically, the memory may be a short-term memory.
The term "improvement" in the present invention refers to any action that alleviates or reduces symptoms of cognitive decline or deterioration, or improves or alleviates symptoms of a subject who has already undergone deterioration or deterioration by using a composition containing the tamsulosin as an active ingredient.
In one embodiment of the present invention, the duration of the step-down abdominal test in the case of rats treated with tamsulosin increases in a dose-dependent manner (Fig. 1), the time taken to find all the water in the 8- And the number of correct errors before the first error is increased (FIG. 2). In the above example, it is confirmed that the test sequence has the memory, learning ability, and spatial perception ability And the effect of improving the cognitive function as shown in Fig.
The pharmaceutical composition for improving the cognitive function of the present invention may selectively increase the current magnitude of the ion channel by the NMDA receptor.
As used herein, the term "NMDA receptor" is an acronym for N-methyl-D-aspartate and is a neuroreceptor in neurons. Protein, which interacts directly with the
In the present invention, the term "ion channel" means a membrane protein that exists in the cell membrane and allows ions to pass through the cell in and out. Specifically, in the present invention, the ion channel is opened and closed by the NMDA receptor.
The term "selectively " in the present invention means that the AMPA receptor, the NMDA receptor, and the Kainate receptor correspond to the ligand-opening type ion channels of the glutamate receptor present in the cerebrum. Among the receptors, AMPA receptor and Kainate Refers to increasing the current magnitude of the ion channel by the NMDA receptor without affecting the ion channel by the receptor.
In the present invention, the term "AMPA receptor" is a subtype of channel-type glutamic acid selectively activated by AMPA (? -Amino-3-hydroxy-5-methylisoxazole-4-propionic acid). The AMPA receptor channel of the higher animal central nervous system normally permeates Na + and K + , and plays an important physiological function that plays a major part of the rapid excitatory synaptic transmission in the central nervous system.
In the present invention, the term "Kainate receptor ", also abbreviated as KARs, is a ligand-releasing ionic receptor that responds to neurotransmitter glutamate.
In another aspect, the present invention provides a pharmaceutical composition for preventing or treating neurodegenerative diseases, which comprises tamsulosin as an active ingredient.
In one embodiment of the present invention, it was confirmed that the mice treated with tamsulosin had excellent effects of improving cognitive functions such as memory, learning ability and spatial perception ability, and in particular, mice treated with tamsulosin in the aged group It was confirmed that the expression of the protein associated with apoptosis was abruptly inhibited and the expression of the protein associated with neuronal tissue development was rapidly induced. As a result, it was confirmed that the composition containing tamsulosin as an active ingredient showed a decrease in cognitive function Can be used to prevent or treat associated neurodegenerative diseases.
In the present invention, the term "neurodegenerative disease" means a disease associated with symptoms of nerve cell degeneration, loss of function, or death.
The term "prevention" in the present invention refers to any action that inhibits or delays the onset of a neurodegenerative disease using a composition comprising the tamsulosin as an active ingredient.
In the present invention, the term "treatment" refers to all actions that control or ameliorate a symptom, a wound, or the like of a neurodegenerative disease by using a composition comprising the tamsulosin as an active ingredient.
Specifically, the neurodegenerative disease may be Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, Huntington's disease, anterior temporal dementia, cortical-basal ganglia, or progressive supranuclear palsy. Specifically, the neurodegenerative disease may be dementia or Alzheimer's disease.
The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.
As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not irritate the organism and does not interfere with the biological activity and properties of the administered compound. Examples of the pharmaceutical carrier which is acceptable for the composition to be formulated into a liquid solution include sterilization and sterilization which are suitable for a living body and include saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol And one or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, a stabilizer and the like may be added.
According to another embodiment of the present invention, the present invention provides a method for improving cognitive function, comprising the step of administering to a subject in need thereof a pharmaceutical composition for improving the cognitive function comprising the tamsulosin as an active ingredient to provide.
The term "individual" as used herein means all animals, including humans, whose cognitive function has been degenerated or deteriorated or may be degraded. By effectively administering the pharmaceutical composition of the present invention to a subject, Or improved. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with a conventional therapeutic agent for improving cognitive function, and can be administered sequentially or simultaneously with conventional therapeutic agents.
The term "administering" of the present invention means introducing a predetermined substance into a patient in an appropriate manner, and the administration route of the composition can be administered through any conventional route as long as it can reach the target tissue. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain, in addition to the composition, at least one excipient such as starch, calcium carbonate, sucrose, Gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, suppositories, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be added in addition to commonly used simple diluents such as water, May be included. The oral composition is preferably formulated so as to coat the active agent or protect it from degradation at the top. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, lozenges, lyophilized formulations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oligo phosphate), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, and microbial growth inhibition (E.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
The composition may be administered in single or multiple doses in a pharmaceutically effective amount. The term "pharmaceutically effective amount" as used herein means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical prophylaxis or treatment, and the effective dose level will depend on the severity of the disease, Activity, the patient's weight, health, sex, sensitivity of the patient to the drug, the time of administration of the composition of the present invention used, the route of administration and the rate of release, the duration of the treatment, Factors and factors well known in the medical arts.
In another aspect, the present invention provides a health food composition for improving the cognitive function comprising tamsulosin as an active ingredient.
Specifically, the cognitive function may be memory, learning or spatial perception. Specifically, the memory may be a long-term memory or a short-term memory, and more specifically, the memory may be a short-term memory.
Since tamsulosin, which is an active ingredient of the composition of the present invention, has already been confirmed to be stable, it can prevent deterioration or deterioration of cognitive function when it is common for a long period of time according to usual eating habits, .
The term "prevention" in the present invention refers to any action that inhibits or delays the degradation or inhibition of cognitive function using a composition comprising the tamsulosin as an active ingredient.
The term "improvement" in the present invention refers to any action that alters the suspicion of cognitive function degeneration or deterioration and the improvement or improvement of symptoms of an already degenerated or depressed individual using the composition comprising the tamsulosin as an active ingredient.
When the composition comprising tamsulosin of the present invention as an active ingredient is used as a food additive, the composition may be added to the food or beverage, or may be used in combination with other food additives. When the food additive of the present invention is added at the time of preparing food or beverage, the addition amount thereof is not particularly limited. However, in the case of long-term ingestion intended for health and hygiene purposes or health control purposes, Or less, and since there is no problem in terms of safety, the active ingredient may be used in an amount of more than the above range.
In addition, the type of the food or beverage is not particularly limited, but includes food or beverage in a conventional sense, preferably meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, etc. Noodles, gums, dairy products including ice cream, various soups, drinks, tea, drinks, alcoholic beverages and vitamin complexes.
When a food additive containing the tamsulosin as an active ingredient of the present invention is added to a food, it is possible to add various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, A colloid thickener, a pH adjusting agent, a stabilizer, a preservative, glycerin, an alcohol, and the like, and the content of the auxiliary component is not particularly limited thereto.
In addition, when a food additive containing tamsulosin as an active ingredient of the present invention is added to beverages, various sweetening agents or natural carbohydrates may be added as additional ingredients such as ordinary beverages. The sweetener may be a natural sweetening agent such as tau Martin or stevia extract or a synthetic sweetening agent such as saccharin and aspartame. The natural carbohydrate may be monosaccharides such as monosaccharides (E.g., glucose, fructose, and the like), disaccharides (e.g., maltose, sucrose, etc.), polysaccharides (e.g., dextrin, cyclodextrin and the like), sugar alcohols (e.g., xylitol, sorbitol, erythritol, Etc., and the content of the natural carbohydrate is not particularly limited.
The health food composition may be processed into any one form selected from the group consisting of tablets, capsules, powders, liquid agents and pills.
As described above, the present inventive testosterone induces neural tissue development without changing the cell death level of the hippocampus and selectively increases the current size of the ion channel by the NMDA receptor, thereby improving memory, learning ability, and spatial perception ability And thus can be usefully used for improving cognitive function and further applicable to the treatment of neurodegenerative diseases.
FIG. 1 shows the results of a step-down avoidance test to determine the effect of tamoxifen on memory. CON is a control group, T-0.001 is 0.001 mg / kg of testosterone The treatment group, T-0.01, showed a 0.01 mg / kg testosterone treatment group, T-0.1, 0.1 mg / kg testosterone treatment group, and T-1, 1 mg / kg testosterone treatment group. The data are expressed as the mean ± standard error of the mean (SEM). * Means P <0.05 when compared to the control group, and § means P <0.05 when compared to the 0.1 mg / kg testosterone treatment group.
Fig. 2 shows the results of a radial 8-arm maze test to investigate the effect of Tomlson on learning ability and spatial perception ability.
FIG. 3 shows the results of the effect on DNA fragmentation in order to examine the effect of tamsulosin on the cell death level.
FIG. 4 shows the results of measurement of the expression level of the protein by Western blotting in order to examine the effect of tamsulosin on Bcl-2 and Bax expression in the hippocampus.
FIG. 5 shows the results of immunohistochemical staining of the number of BrdU-positive cells in order to examine the effect of the testosterone on the development of nerve tissue in the hippocampus.
FIG. 6 shows the results of measuring the expression level of the protein by Western blotting in order to examine the effect of tamsulosin on the expression of BDNK and TrkB in the hippocampus.
Figure 7 shows the effect of tamsulosin on NMDA receptor-induced ion flux in hippocampal CA1 neurons. (A) shows a typical graph of the current induced as the concentration of NMDA increases, (B) shows a graph of a dose-dependent graph of NMDA-induced ion current, A representative graph for NMDA induced currents of 100 쨉 m when treated with testosine is shown, and (D) shows a graph of the dose-dependent effect of tamsulosin on NMDA-induced ion current.
Figure 8 relates to the effect of tamsulosin on AMPA induced ion flux in hippocampal CA1 neurons. (A) shows a typical graph of the induced current as the concentration of AMPA is increased, (B) shows a representative graph of AMPA-induced ion current of 100 탆 when 0.3 탆 of tomosin is treated, and ) Is a histogram showing the mean ± standard error of the mean (SEM).
Figure 9 relates to the effect of tamsulosin on kainate-induced ion flux in the hippocampal CA1 neuron. (A) shows a typical graph of the current induced as the concentration of the carbonate is increased, and (B) shows a representative graph of a carbonate ion-induced ion current of 100 [mu] m when 0.3 [mu] C) shows the histogram showing the mean ± standard error of the mean (SEM).
Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
Example 1: Experimental animals and Tom's God process
All experiments were carried out in accordance with the animal protection guidelines of the National Institutes of Health (NIH) and the Korean Medical Association. The Sprague-Dawley rats used in the experiment were 40 young-aged rats and 40 old-aged rats aged 25 months. Rats were randomly assigned to 8 rats in each group (control group (T-0.01), 0.01 mg / kg of testosterone treated group (T-0.001), 0.01 mg / kg of testosterone treated group -0.1), and 1.0 mg / kg of testosterone treated group (T1). The rats in the group treated with tamsulosin were orally administered the respective positive amounts of tamsulosin (Harnal ® , Astellas Pharma Inc., Tokyo, Japan) once a day for four consecutive weeks.
Example 2: Step-down Ebonidans Test( Step - down avoidance test )
To measure short-term memory, the duration of the step-down speech test was measured. Rats were placed on a 7 x 25-cm platform 2.5 cm high. The platform surface is made of 45 × 25-cm grid-like parallel stainless steel bars, with a diameter of 0.1 cm and a spacing of 1 cm.
The rats were trained using a step-down approach for 4 weeks after the start of the treatment with testosterone. During the training time, the animals were immediately descended on a 0.2-mA scrambled floor impact for 2 seconds. After two hours of training, the duration (in seconds) of each group was measured. The duration was defined as the elapsed time until the rat descended from the plaid surface on the platform and placed all four feet on the floor. The duration over 180 seconds was calculated as 180 seconds.
As a result, the duration in step-down annealing test increased in a dose-dependent manner, as can be seen in Fig. 1, when the test strain was treated. The above results indicate that 4 weeks of tamsulosin treatment improves memory in rats.
Example 3: 8-way radial labyrinth experiment Radial 8- arm maze test )
We tested the learning ability and the spatial perception ability using an 8 - way radial labyrinth experiment. The radial labyrinth device is composed of an octagonal plate (
The rats were trained three times before the 8-way radial lab test. The training was conducted on days 21, 24, and 27 after the start of the treatment of the testosterone. During the training session, the rats allowed water to be taken for 24 hours, then allowed to go for 5 minutes after each hour.
After the training, the test was performed at 4 weeks after the start of the testosterone treatment. The time taken to find the water at the end of the arm was measured, and the test was terminated when the mice found water in all eight cancers or when the elapsed time was greater than 8 minutes. The number of correct selections before the first error was calculated, and the number of re-entry into the previously visited arm was calculated as an error.
As a result, as can be seen from Fig. 2, the treatment of the testros decreased the time taken to find all the water and the number of errors before eight successful runs, and increased the number of correct selections before the first error. The above results indicate that 4 weeks of tamsulosin treatment improves the learning and spatial perception ability in rats.
Example
4: Seahorse
In the dental brainstem
Tom's God
TUNEL
- confirmation of the effect on the number of positive cells
4-1. tissue( tissue )
The animals were sacrificed immediately after measuring the duration of the step-down abdominal test. They were anesthetized with Zoletil 50 ® (10 mg / kg, ip; VibacLaboratories, Carros, France), and 50 mM phosphate-buffered saline (PBS) Buffer (PB, pH 7.4) was fixed with a solution consisting of 4% paraformaldehyde. The brain was removed, stored overnight using the same fixative as described above, and transferred to 30% sucrose for cryoprotection. For TUNEL staining, 40 mu m thick corona sections were prepared using a cryoprotectant (Leica, Nussloch, Germany). An average of 10 sections were collected from the hippocampal dentate gyrus of each rat.
4-2. TUNEL dyeing
According to the manufacturer's protocol, in order to confirm cell death (Ko et al, 2009;. . Jeon et al, 2014), the DNA fragmentation was observed using the In Situ Cell Death Detection Kit ® ( Roche, Mannheim, Germany). The sections were postfixed and washed with ethanol-acetic acid (2: 1). After that, they were cultured with Proteinase K (100 μg / ml), washed with water and cultured in 3% H 2 O 2 . Thereafter, the cells were osmoticized with 0.5% Triton X-100, rinsed again, and then cultured in a TUNEL reaction mixture. The sections were then washed and then observed with Converter-POD containing 0.03% 3,3'-diaminobenzidine (DAB). Mayer's hematoxylin (DAKO, Glostrup, Denmark) was used as a counter-stain. The slides were dried naturally at room temperature overnight, dried using ethanol concentration, and cover slipped using Permount® (Fisher Scientific, New Jersey, NJ, USA).
4-3. result
Figure 3 (above) relates to a micrograph showing TUNEL-positive in the dental hypothalamus of the hippocampus. Treatment with testosterone did not have a significant effect on the number of TUNEL-positive cells (Fig. 3, bottom). The above results indicate that 4 weeks of treatment with tamsulosin does not induce hippocampal cell death.
Example
5:
Tomslo
In the sea horse
Bcl
-2 and
Bax
Identification of effects on expression
In order to examine the effect of tamsulosin on apoptosis, the expression level of Bcl-2 and Bax, which are related to apoptosis, in rat hippocampus of young group and aged group was measured by Western blot.
As can be seen in FIG. 4, in the young group and in the rats of the older group, Bcl-2 protein associated with apoptosis was more expressed with treatment with testosterin, and the expression level of Bax protein was decreased Respectively. In addition, it was confirmed that the ratio of Bcl-2 / Bax increases with each increase in the throughput of testosterone. This indicates that treatment with testosterone does not induce cell death of the hippocampus, indicating that the effect is greater in aged rats.
Example
6:
Tomslo
hippocampus
In the dental brainstem
Identification of effects on nervous system development
In addition, the number of BrdU-positive cells in the dental brainstem of rats in the young and old groups of mice was measured using immunohistochemistry and staining to determine the effect of tamsulosin on nerve tissue development .
As can be seen in FIG. 5, in both young and old groups of rats, the number of BrdU-positive cells was found to be increased dependent on the dosage of tomoskine, and in particular, And the number of samples was increased rapidly. The results indicate that treatment with testrosin induces the development of nerve tissue, particularly in aged rats.
Example
7:
Tomslo
In the sea horse
BDNK
And
TrkB
Effect on expression
Western blot analysis of the expression of BDNK and TrkB in the hippocampus of young rats and elderly rats in order to examine the effect of tamsulosin on neurogenesis.
As shown in FIG. 6, the expression of BDNK and TrkB was increased in a dose-dependent manner in the mouse hippocampus of the young group and the aged group, and in particular, . The above results also indicate that treatment with tamsulosin induces neurogenesis and is highly effective in aged rats.
Example
8:
Tomslo
NMDA
- induced ion current,
AMPA
- Determination of the effect of induced ion current and kainate-induced ion current
8-1. hippocampus CA1 Manufacture of neurons
The hippocampal CA1 neurons were isolated using the following techniques. Both sex (sex) 10- to 15-day-old Sprague-Dawley rats with Zoletil ® 50 - were sacrificed to inducing anesthesia (50 mg / kg, im) . The brains of the rats were removed and transverse slices (thickness 400 쨉 m) were prepared with a microslicer (DTK-1000, DSK, Tokyo, Japan). The slices were pre-incubated at room temperature for 30 minutes in aqueous hydrogen peroxide (95% O 2 and 5% CO 2 ). Thereafter, the slices were treated with pronase (protease XIV, 1 mg / 6 ml of peroxidized culture solution) at 32 ° C for 40 to 60 minutes and then cultured for 1 hour in enzyme-free culture Respectively.
The hippocampal CA1 site was identified with a binocular microscope (SZ-ST, Olympus, Tokyo, Japan) and a microhole was drilled through the slices with an electrolytically well-dosed needle. The perforated hippocampal CA1 neurons were mechanically separated into a 35-mm plastic culture dish (Falcon, Franklin Lakes, NJ, USA) filled with a standard solution and lightly flashed with a small glass Pasteur pipette. The separation procedure was carried out using an inverted phase contrast microscope (CK-2, Olympus, Tokyo, Japan). The separated neurons were attached to the bottom of the container within 20 minutes. These cells were preserved for electrophysiological studies for more than 6 hours after isolation.
8-2. Preparation of culture solution
Ionic composition of the culture solution is as follows (in mM): NaCl 124, KCl 5 ,
8-3. Electrophysiological measurement
Electrophysiological recordings were performed in nystatin-perforated recording mode under voltage clamp conditions. The patch pipette was manufactured from a glass capillary having an outer diameter of 1.5 mm in a two-stage puller (PB-7, Narishige, Tokyo, Japan). The resistance between the recording electrode filling the inner pipette solution and the reference electrode was 6-8 M?. After formation of a stable perforation patch, the continuous resistance was in the range of 16 to 25 M OMEGA. Electrical simulation, electrical record and electrical filtration (at 2.9 kHz) were obtained with an EPC-7 patch-clamp amplifier (List-Electronic, Darmstadt / Eberstadt, Germany). The current and voltage were also observed using a pen recorder (Recti-Horiz-8K, NEC San-ei, Tokyo, Japan). All experiments were performed at room temperature (22-24 ° C).
8-4. result
8-4-1. Tomslo NMDA - Effect on induced current
NMDA induced current in a dose-dependent manner (Figs. 7A and 7B). The magnitude of ion current induced by 100 .mu.M NMDA alone was used as a control value. Initial amplification of NMDA-induced ionic currents appears to vary to less than 5% during the recorded period until the testosterone is processed. The magnitude of the NMDA-induced ionic currents was enhanced in a dose-dependent manner by simultaneous treatment with the testosterone (Figs. 7C and 7D). These results show that tomrozine elevates NMDA-induced ion currents in hippocampal CA1 neurons.
8-4-2. Tomslo AMPA - Effect on induced ion current
AMPA induced current in a dose dependent manner (Figure 8A). The magnitude of the current induced by 100 μM AMPA alone was used as the control value. The initial amplification of the AMPA induced ion current is seen to vary to less than 5% during the recorded period. The AMPA induced ionic current was not changed by simultaneous application of 0.3 [mu] m tetrasinosine (Figs. 8B and 8C). These results indicate that tamsulosin does not have a significant effect on AMPA induced ion currents in hippocampal CA1 neurons.
8-4-3. Tomslo kainate - Effect on induced ion current
The kainate caused the current to flow inward in a dose-dependent manner (Fig. 9A). The magnitude of the current induced by 100 mu m kainate alone was used as the control value. The initial amplification of the kaonate-induced ionic current is seen to vary to less than 5% during the recorded period. The carbonate ion-induced ion current was not changed by simultaneous application of 0.3 [mu] m tetrasinosine (Figs. 9B and 9C). These results indicate that tamsulosin does not have a significant effect on the kinetics induced ion current in hippocampal CA1 neurons.
Taken together, the above experimental results show that the present inventive testosterone induces the generation of nerve tissue without changing the cell death level and selectively increases the current magnitude of the ion channel by the NMDA receptor, It shows that cognitive function can be improved by increasing perceptual ability.
From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.
Claims (7)
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